Multiscale nuclear mechanobiology within the skin: from biophysical cues to epigenetic effects

皮肤的表皮形成了对外界环境必不可少的物理屏障，并不断暴露在复杂的生物力学力下。众所周知，机械和生物物理信号调节多种细胞功能，如生长、迁移和存活，但皮肤细胞感知这些力的分子水平机制仍知之甚少。由于细胞核是包装DNA的中心细胞器，并且这种内部结构定义了基因表达的特定模式，我们假设细胞核是细胞内主要的机械传感元件：机械诱导的核形状变化影响基因的内部结构和转录。事实上，我们的初步数据表明，暴露于特定物理线索的角化细胞显示出核大小和形状的变化，而这些核形态的变化与DNA结构的改变有关。该项目的总体目标是了解力是如何从外部环境传递到细胞核的，并确定随后对皮肤表皮内的核结构、基因表达和细胞功能的影响。我们将使用先进的生物物理和成像技术将力应用于单细胞，并使用系统生物学方法来分析DNA结构和基因表达的变化。此外，我们将测试细胞内部结构（如细胞骨架）的作用，以获得对这些过程的机械洞察。最后，我们将研究核机械传感在更复杂的人体皮肤3D模型中的影响。这个项目的成功完成将为细胞如何感知机械力，特别是细胞核的作用提供基础和重要的见解。这些知识将促进我们对正常皮肤生理和机械功能的理解。拟议项目的其他影响包括开发新的生物物理工具和技术，与学术界和工业界建立新的合作关系，以及为参与的科学家提供多学科培训。未来的研究可能会涉及核结构的其他方面的研究，并检查这些机械转导途径在皮肤疾病（如水泡、疤痕或癌症）中的作用。

The epidermis of the skin forms an essential physical barrier to the external environment, and it is continuously exposed to complex biomechanical forces. While it is well known that mechanical and biophysical cues regulate diverse cellular functions, such as growth, migration, and survival, the molecular level mechanisms by which cells within the skin sense these forces remains poorly understood. As the nucleus is the central organelle within which DNA is packaged and this internal structure defines specific patterns of gene expression, we hypothesise that the nucleus is a major mechano-sensing element within the cell: Mechanically induced changes in nuclear shape influence the internal structure and transcription of genes. Indeed, our preliminary data indicate that keratinocytes exposed to defined physical cues display changes in nuclear size and shape, and these changes in nuclear morphology correlate with altered DNA structure.The overall objective of the proposed project is to understand how forces are transmitted from the external environment to the nucleus and to determine the subsequent effects on nuclear structure, gene expression, and cell function within the epidermis of the skin. We will use advanced biophysical and imaging techniques to apply forces to single cells, and systems biology methodologies to analyse the changes in DNA structure and gene expression. In addition, we will test the role of internal cellular structures, such as the cytoskeleton, to gain mechanistic insight into these processes. Finally, we will investigate the influence of nuclear mechano-sensing in more complex 3D models of human skin.The successful completion of this project will provide fundamental and significant insights into how cells sense mechanical forces, in particular the role of the nucleus. This knowledge will advance our understanding of normal skin physiology and mechanical function. Additional impacts of the proposed project include the development of new biophysical tools and technologies, building new collaborations with academics and industry, and multi-disciplinary training for the scientists involved. Future studies following on from this work could involve investigation of additional aspects of nuclear structure and examining the role of these mechanotransduction pathways in skin diseases such as blistering, scarring, or cancer.